Increasing evidence suggests that the myocardial effects of metabolic diseases (including obesity, metabolic syndrome, and diabetes) are independent and potent contributors to cardiac morbidity and mortality. However, the molecular and cellular pathways that link metabolic disease and cardiac dysfunction remain poorly understood. Funding from the R24 seed mechanism would catalyze the formation of a new interdisciplinary investigative team to examine the mechanistic connections between metabolism and heart disease. Specifically, we propose to investigate the roles of retinoids, as well as their binding proteins and relevant receptors, as markers and mediators of both metabolic disease and cardiac dysfunction with a particular focus on their effects on insulin action. This application brings together scientists with diverse and complementary expertise including clinical and basic investigation in endocrinology, metabolism and cardiology. Together this group has the potential to characterize the alterations in retinoids and associated proteins in metabolic diseases in both animal models and clinical cohorts, and to understand the pathophysiological consequences of these alterations for cardiac dysfunction in the context of cardiomyocyte cell biology, integrative physiology in animal models, and human pathophysiology. Approaches to be employed include metabolic profiling of clinical and animal samples, careful phenotyping in clinical cohorts, and gain- and loss-of-function genetic experiments in animal models. We anticipate that the patterns identified will not only provide potentially useful biomarkers of metabolic disease and/or cardiac dysfunction but could also identify novel targets for intervention in this context. The ability to compare results across a broad range of human, cellular, and murine models already established in applicant laboratories will provide important synergies, allowing us to identify and study common patterns with functional consequences. We believe that these synergistic, collaborative interactions provide a unique and powerful opportunity for major advances in the area. PUBLIC HEALTH RELEVANCE: Heart disease is a major cause of illness and death throughout the world. Heart disease is often linked to diabetes, and people with diabetes have worse outcomes when they develop heart disease than non- diabetic people. We will form a new interdisciplinary team of cardiology and diabetes researchers to determine novel molecular mechanisms underlying the association of diabetes with poor function of the heart. We anticipate our research will ultimately lead to earlier diagnosis and treatment of heart disease.